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Cerebellar ataxia with sensory ganglionopathy; does autoimmunity have a role to play?

Cerebellum & Ataxias20174:20

https://doi.org/10.1186/s40673-017-0079-1

  • Received: 7 November 2017
  • Accepted: 8 December 2017
  • Published:

Abstract

Background and purpose

Cerebellar ataxia with sensory ganglionopathy (SG) is a disabling combination of neurological dysfunction usually seen as part of some hereditary ataxias. However, patients may present with this combination without a genetic cause.

Methods

We reviewed records of all patients that have been referred to the Sheffield Ataxia Centre who had neurophysiological and imaging data suggestive of SG and cerebellar ataxia respectively. We excluded patients with Friedreich’s ataxia, a common cause of this combination. All patients were screened for genetic causes and underwent extensive investigations.

Results

We identified 40 patients (45% males, mean age at symptom onset 53.7 ± 14.7 years) with combined cerebellar ataxia and SG. The majority of patients (40%) were initially diagnosed with cerebellar dysfunction and 30% were initially diagnosed with SG. For 30% the two diagnoses were made at the same time. The mean latency between the two diagnoses was 6.5 ± 8.9 years (range 0–44). The commonest initial manifestation was unsteadiness (77.5%) followed by patchy sensory loss (17.5%) and peripheral neuropathic pain (5%).

Nineteen patients (47.5%) had gluten sensitivity, of whom 3 patients (7.5%) had biopsy proven coeliac disease. Other abnormal immunological tests were present in another 15 patients. Six patients had malignancy, which was diagnosed within 5 years of the neurological symptoms. Only 3 patients (7.5%) were classified as having a truly idiopathic combination of cerebellar ataxia with SG.

Conclusion

Our case series highlights that amongst patients with the unusual combination of cerebellar ataxia and SG, immune pathogenesis plays a significant role.

Keywords

  • Ganglionopathy
  • Cerebellar ataxia
  • Gluten
  • Autoimmunity

Introduction

Ataxia is a term used to describe unsteadiness and poor co-ordination of movements. It can occur secondary to cerebellar dysfunction (cerebellar ataxia) or because of dysfunction within the peripheral or central sensory pathways (sensory ataxia).

Cerebellar ataxia can be inherited (e.g. Friedreich’s ataxia and spinocerenellar ataxias, known as SCAs) or acquired (e.g. gluten ataxia and paraneoplastic) [1].

Sensory ataxia is commonly seen in neuropathies that involve sensory fibers and are more prominent in pure sensory neuropathies involving the dorsal root ganglia, commonly referred to as sensory ganglionopathies (SG) [2]. Causes of SG can be inherited (e.g. mitochondrial disorders) or acquired (e.g. paraneoplastic) [35].

Cerebellar ataxia combined with SG is a relatively rare neurological combination, which can sometimes be seen in the context of hereditary ataxias [2] (e.g. Friedreich’s ataxia and SCA4, mitochondrial disease and Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) [6]) or as a result of exposure to toxins (e.g. amiodarone [7]).

We present a case series of patients with this unusual combination, in an attempt to shed light into possible underlying aetiology.

Methods

Standard protocol approvals, registrations, and patient consents

This is a retrospective observational case series of patients regularly attending the Ataxia clinic based at the Royal Hallamshire Hospital (Sheffield, UK). The South Yorkshire Research Ethics Committee has confirmed that no ethical approval is indicated given that all investigations were clinically indicated and did not form part of a research study.

Patient selection

All recruited patients had clinical and neuroimaging evidence of progressive cerebellar dysfunction as well as clinical and neurophysiological evidence of SG.

Neurophysiological assessments

All patients underwent detailed nerve conduction studies including median (sensory and motor), ulnar (sensory and motor), superficial radial (sensory), sural (sensory), superficial peroneal (sensory) and tibial (motor). All sensory nerve conduction studies were performed bilaterally. On all occasions supramaximal stimulation of the nerves was performed.

The diagnosis of SG was based on the established diagnostic criteria [8, 9]. Clinically patients that presented with signs and symptoms of patchy sensory symptoms and reduced or absent tendon reflexes underwent nerve conduction studies. SG was confirmed electrophysiologically with complete absence of sensory nerve action potentials (SNAPs) or asymmetrical sensory fiber involvement (asymmetrical SNAPs) with no motor involvement.

Neuroimaging assessments

All patients underwent a magnetic resonance imaging (MRI) of the brain and a magnetic resonance spectroscopy (MRS) of the cerebellum. The latter technique is validated and is used to determine the presence of cerebellar dysfunction, even in the absence of cerebellar atrophy [10]. We measured the N-acetyl-aspartate/creatine (NAA/Cr) ratios in the vermis and the cerebellar hemispheres. Only patients with cerebellar atrophy and/or abnormal NAA/Cr ratios in either the vermis or the hemispheres and/or cerebellar atrophy in the MRI where considered as having cerebellar dysfunction.

Serologic testing

Serological testing was performed and included extensive testing for possible acquired causes of cerebellar ataxia and sensory ganglionopathy. Human leukocyte antigen (HLA) typing was performed by the regional blood-transfusion service.

Genetic testing

Patients with early onset cerebellar ataxia and/or family history of ataxia were tested genetically for possible genetic causes. A muscle biopsy was done in patients with a suspected mitochondrial disease. By default we did not include in this case series patients with Friedreich’s ataxia (FA) as this is a well known cause of this combination of neurological deficits.

Enteropathy

Patients with gluten sensitivity underwent gastroscopy and duodenal biopsy to establish the presence of enteropathy. All biopsies were histologically assessed for evidence of enteropathy (triad of villous atrophy, crypt hyperplasia, and increase in intraepithelial lymphocytes).

Statistical analysis

A database was developed using the statistical software package SPSS (version 23.0 for Macintosh). Descriptive statistics were examined for each variable.

Results

Clinical characteristics

We identified 40 patients (45% males) with combined cerebellar ataxia and sensory ganglionopathy. Mean age at onset of the symptoms was 53.7 ± 14.7 years (range 8–80) and mean age at first presentation was 56.6 ± 13.5 years (range 14–81). At presentation, the majority of patients (40%) were diagnosed with cerebellar ataxia and 30% were diagnosed with SG. For 30% the two diagnoses were made at the same time. The mean latency between the two diagnoses was 6.5 ± 8.9 years (range 0–44). The commonest initial manifestation was unsteadiness (77.5%) followed by patchy sensory loss (17.5%) and peripheral neuropathic pain (5%).

Neurophysiology

Sixteen patients (40%) had absent SNAPs, whereas the rest had asymmetrical SNAPs. No patients had abnormal compound muscle action potentials (CMAPs). Table 1 summarizes the neurophysiological characteristics of a typical patient with asymmetrical SNAPs (Patient 1) and of a patient with completely absent SNAPs (Patient 2) from these series.
Table 1

Neurophysiological characteristics of a typical patient with asymmetrical SNAPs (Patient 1) and of a patient with completely absent SNAPs (Patient 2) from these series

Subject

NCS

Parameter

Median

CMAP

Ulnar (ADM)

CMAP

Tibial

CMAP

Median

SNAP

Ulnar

SNAP

Radial

SNAP

Sural

SNAP

Superficial Peroneal

SNAP

 

Side

(R)

(R)

(R)

(R)

(L)

(R)

(L)

(R)

(L)

(R)

(L)

(R)

(L)

Patient 1

(Asymmetric SNAPs)

46Y, Female

Amplitude

14.1 mV

10.7 mV

9.2 mV

17.4 μV

6.1 μV

3.1 μV

5.7 μV

18.4 μV

12.4 μV

21.5 μV

12.8 μV

7.7 μV

3.4. μV

Conduction velocity

60 m/s

(Elbow-Wrist)

60 m/s

(Below elbow – Wrist)

70 m/s

(Above elbow – below elbow)

NC

56 m/s

(Digit III –Wrist)

60 m/s

(Digit III –Wrist)

58 m/s

(Digit V –Wrist)

57 m/s

(Digit V–Wrist)

58 m/s

(Forearm- Snuff Box

55 m/s

Forearm- Snuff Box

48 m/s

Calf – lateral malleolus

48 m/s

Calf – lateral malleolus

48 m/s

Leg – Dorsum of the foot

47 m/s

Leg – Dorsum of the foot

Patient 2

(Absent SNAPS)

67Y, Male

Amplitude

8.3 mV

6.3 mV

3.0 mV

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Conduction velocity

54 m/s

(Elbow-Wrist)

48 m/s

(Below elbow – Wrist)

59 m/s

(Above elbow – below elbow)

NC

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NCS nerve conduction studies, CMAP compound muscle action potential, SNAP sensory nerve action potential, ADM abductor digiti minimi, R right, L left, NC not checked, NR not recordable, NA not applicable

Neuroimaging characteristics

All patients had abnormal MRS at diagnosis. Fifteen patients (37.5%) had low NAA/Cr ratio only in the vermis (<0.96) and 6 patients (15%) had low NAA/Cr ratio only in the hemispheres (<1). Nineteen patients (47.5%) had low NAA/Cr ratio in both the vermis and the hemispheres. Only 55% of the patients had cerebellar atrophy in the initial MRI.

Evidence of autoimmunity

Nineteen patients (47.5%) had gluten sensitivity, of whom 3 patients (7.5%) had biopsy proven coeliac disease. Other abnormal immunological tests were present in another 15 patients (i.e. GAD, ANA etc.), of whom 4 patients (10%) had biopsy proven Sjogren’s syndrome.

Cancer

Nine patients had a history or developed malignancy (3 bowel, 1 melanoma, 1 light chain myeloma, 2 ovarian, 1 uterus and 1 of unknown primary location). However, only in 6 patients of them the malignancy was diagnosed within 5 years of the neurological symptoms. Anti-Yo antibodies were found in one patient.

Genetic causes

Nineteen patients were investigated for familial ataxias using next generation sequencing ataxia panel containing 42 genes. In selected patients genetic testing for common mitochondrial mutations (including POLG1) and muscle biopsies were performed. For two of them a genetic cause was identified (one mitochondrial, one SCA18).

HLA type

HLA typing was performed in 34 patients. Of them, 18 patients (52.9%) had the DQ2 type, 6 patients (17.6%) had the DQ8 type, 9 patients (26.5%) had the DQ1 type and 1 patient (2.9%) had another HLA type.

Truly idiopathic cases

After extensive immunological and genetic screening, only 3 patients (7.5%) were classified as having a truly idiopathic combination of cerebellar ataxia with SG (Table 2).
Table 2

Clinical, neuroimaging and serological characteristics of all patients

Gender

Age at 1st presentation

First symptoms

Age at first symptoms

First diagnosis

Second symptoms

Age at second diagnosis

MRI

Abnormal

MRS

SNAPs

Gluten serology

Duodenum biopsy

HLA

Other evidence of autoimmunity

Cancer

Age at cancer diagnosis

Genetics

Truly idiopathic

Female

48

Unsteadiness in the dark

48

SG

Worsening of balance

63

Normal for age

Vermis and hemisphere

Absent

Negative

N/A

DQ2

ENA+ ANA+, Crohn’s

  

Negative

 

Female

59

Patchy numbness

57

SG

No new symptoms

60

Normal for age

Vermis

Asymmetrical

Positive

CD

DQ2

TPO+, dsDNA+, RF+

Ovarian

38

  

Male

40

Patchy numbness

38

SG

Worsening of balance

62

Normal for age

Vermis

Absent

Positive

Normal

DQ2

P-ANCA+, ANA+, GM1+, Sarcoidosis

    

Male

60

Patchy burning pain

59

SG

No new symptoms

65

Normal for age

Hemisphere

Asymmetrical

Positive

Normal

DQ2

     

Female

76

Unsteadiness/Numbness

76

SG

Worsening of balance

84

Normal for age

Hemisphere

Asymmetrical

Positive

CD

DQ2

     

Male

49

Patchy numbness

49

SG

No new symptoms

72

Normal for age

Hemisphere

Absent

Negative

N/A

DQ1

ANA+, RF+

  

Negative

 

Male

52

Pain in feet

49

SG

Worsening of balance

70

Normal for age

Vermis

Asymmetrical

Negative

N/A

DQ1

ANA+, P-ANCA+, SACE+

    

Female

55

Patchy numbness

55

SG

Worsening of balance

69

Normal for age

Vermis

Asymmetrical

Negative

N/A

Not done

ANA+, ENA+ (Sjogren’s)

    

Male

67

Unsteadiness

64

SG

Worsening of balance

68

Cerebellar atrophy

Vermis

Absent

Negative

N/A

DQ2

ANA+, P-ANCA+, MGUS

    

Female

61

Patchy pain

61

SG

Worsening of balance

67

Normal for age

Hemisphere

Asymmetrical

Negative

N/A

Not done

ANA+, ENA+ (Sjogren’s)

    

Female

58

Patchy numbness

57

SG

Worsening of balance

74

Normal for age

Hemisphere

Asymmetrical

Negative

N/A

Other

    

Yes

Female

35

Patchy numbness

35

SG

Worsening of balance

49

Normal for age

Vermis and hemisphere

Asymmetrical

Negative

N/A

Not done

ANA+, ENA+ (Sjogren’s)

    

Female

42

Unsteadiness

42

Cerebellar ataxia

Patchy sensory loss

46

Cerebellar atrophy

Vermis and hemisphere

Asymmetrical

Negative

N/A

DQ1

Anti-Yo+

Ovarian

41

  

Male

14

Unsteadiness

14

Cerebellar ataxia

Worsening of balance

58

Cerebellar atrophy

Vermis

Asymmetrical

Positive

CD

DQ2

GAD+

  

Mitochondrial

 

Female

57

Unsteadiness/Dizziness

55

Cerebellar ataxia

Sensory symptoms

69

Cerebellar atrophy

Vermis

Absent

Positive

Normal

DQ1

GAD+

  

SCA18

 

Male

52

Unsteadiness

51

Cerebellar ataxia

Sensory symptoms

57

Cerebellar atrophy

Vermis and hemisphere

Absent

Positive

Normal

DQ8

   

Negative

 

Female

50

Unsteadiness/

Slurred speech

47

Cerebellar ataxia

Sensory symptoms

54

Cerebellar atrophy

Vermis and hemisphere

Asymmetrical

Positive

Not done

DQ2

RF+

  

Negative

 

Male

44

Unsteadiness

39

Cerebellar ataxia

No new symptoms

46

Cerebellar atrophy

Vermis

Asymmetrical

Positive

Normal

DQ8

   

Negative

 

Female

54

Unsteadiness

53

Cerebellar ataxia

Sensory symptoms

60

Cerebellar atrophy

Vermis and hemisphere

Asymmetrica

Positive

Normal

DQ2

 

Colon

69

Negative

 

Male

67

Unsteadiness

54

Cerebellar ataxia

No new symptoms

76

Cerebellar atrophy

Vermis and hemisphere

Absent

Positive

Normal

DQ2

ANA+

  

Negative

 

Male

66

Unsteadiness

66

Cerebellar ataxia

No new symptoms

67

Cerebellar atrophy

Vermis and hemisphere

Absent

Negative

N/A

DQ2

ANA+

Bowel

68

  

Female

66

Unsteadiness

63

Cerebellar ataxia

Sensory symptoms

68

Normal for age

Vermis and hemisphere

Absent

Negative

N/A

DQ2

   

Negative

Yes

Female

65

Unsteadiness

59

Cerebellar ataxia

Patch sensory loss

68

Cerebellar atrophy

Vermis

Absent

Negative

N/A

DQ8

C-ANCA+, MGUS

Myltiple myeloma - light chain

70

Negative

 

Female

46

Unsteadiness

46

Cerebellar ataxia

Patchy sensory loss

58

Cerebellar atrophy

Vermis

Asymmetrical

Negative

N/A

DQ1

TPO+

  

Negative

 

Female

66

Unsteadiness

64

Cerebellar ataxia

No new symptoms

69

Normal for age

Vermis and hemisphere

Asymmetrical

Negative

N/A

DQ2

   

Negative

Yes

Female

68

Unsteadiness

67

Cerebellar ataxia

Sensory symptoms

69

Normal for age

Vermis and hemisphere

Absent

Negative

N/A

DQ2

ANA+, TPO+

    

Male

81

Unsteadiness

79

Cerebellar ataxia

Worsening of balance

85

Normal for age

Vermis and hemisphere

Asymmetrical

Negative

N/A

Not done

MGUS

Melanoma/

Possibly prostate

86

  

Female

29

Unsteadiness

8

Cerebellar ataxia

Sensory symptoms

33

Cerebellar atrophy

Vermis and hemisphere

Asymmetrical

Positive

Normal

DQ2

OCB+, TPO+, GAD+ (one occasion only)

  

Negative

 

Male

43

Unsteadiness

34

Both at the same time

 

43

Cerebellar atrophy

Hemisphere

Asymmetrical

Positive

Normal

DQ2

RF+

    

Female

61

Unsteadiness/Numbness

60

Both at the same time

 

61

Cerebellar atrophy

Vermis

Absent

Positive

Normal

DQ1

 

Malignancy of unknown primary location

64

Negative

 

Female

81

Unsteadiness

80

Both at the same time

 

81

Cerebellar atrophy

Vermis

Asymmetrical

Positive

Normal

Not done

     

Male

51

Unsteadiness/Numbness

51

Both at the same time

 

51

Cerebellar atrophy

Vermis and hemisphere

Asymmetrical

Positive

Normal

DQ1

     

Female

55

Unsteadiness/Pain

49

Both at the same time

 

55

Cerebellar atrophy

Vermis

Absent

Negative

N/A

DQ1

GAD+, P-ANCA+

Uterus

39

Negative

 

Male

64

Unsteadiness

54

Both at the same time

 

64

Cerebellar atrophy

Vermis and hemisphere

Absent

Negative

N/A

DQ8

MGUS

  

Negative

 

Male

70

Unsteadiness

67

Both at the same time

 

70

Normal for age

Vermis

Absent

Negative

N/A

DQ1

C-ANCA+

    

Male

54

Unsteadiness

49

Both at the same time

 

54

Cerebellar atrophy

Vermis and hemisphere

Asymmetrical

Negative

N/A

DQ2

TPO+

    

Female

70

Unsteadiness

69

Both at the same time

 

70

Normal for age

Vermis and hemisphere

Asymmetrical

Negative

N/A

Not done

ANA+, ENA+ (Sjogren’s), RF+

Bowel

71

  

Male

57

Unsteadiness

55

Both at the same time

 

57

Cerebellar atrophy

Vermis

Absent

Positive

Normal

DQ2

   

Negative

 

Male

61

Unsteadiness/Numbness

61

Both at the same time

 

62

Normal for age

Vermis and hemisphere

Asymmetrical

Positive

Normal

DQ8

ENA+

    

Female

69

Unsteadiness

64

Both at the same time

 

69

Cerebellar atrophy

Vermis and hemisphere

Asymmetrical

Positive

Normal

DQ8

P-ANCA+

    

Discussion

Our case series highlights that amongst patients with cerebellar ataxia and sensory neuronopathy, where a genetic or a malignant cause is not identified, immune pathogenesis is a likely cause. In fact out of 40 patients, only 2 were found to have a genetic cause and only 6 patients had malignancy, which was diagnosed within 5 years of their symptoms. From the remaining 32 patients the vast majority (91%) had evidence of autoimmunity and only 3 patients (9%) were classified as truly idiopathic.

Whether considering the cut-off of 5 years for a neurological syndrome to be classified as paraneoplastic is a matter of debate [11]. This time period has been based on reports showing that in the majority of cases the interval between the paraneoplastic neurological syndrome and the diagnosis of malignancy is less than 5 years [11]. However in our case series, there are patients who exceed this interval. The type of malignancy, however, may influence this interval.

The HLA type has been linked to predisposition to autoimmunity. In our case series 70.5% of patients had the DQ2 or the DQ8 HLA subtypes, which are known to be associated with autoimmunity. This percentage is significantly higher compared to the 40% of the general population [12]. In addition, in our cohort, evidence for autoimmunity (serological evidence of gluten sensitivity and/or positive other antibody titers) was present in 90% of the patients.

Our findings should be interpreted with some caution given the limitations of our design. Firstly, as this is a retrospective observational case series of patients regularly attending our Ataxia clinic not all patient’s had full genetic screening, which means that the percentage of genetic causes might be higher than the one we reported. However, the bias is probably minimized by the fact that we genetically tested patients with early onset and/or family history of ataxia and SG. When clinically suspected, patients also underwent genetic testing for mitochondrial diseases including muscle biopsies. Despite this it is possible that in some patients mitochondrial aetiology [13, 14] may have been missed. Secondly, we haven’t routinely been examining for the vestibulo-ocular reflex and therefore cases of CANVAS may have been missed. However, our understanding is that most cases with CANVAS, unlike the series here, tend to have a family history.

Both cerebellar ataxia (gluten ataxia) and sensory ganglionopathy in isolation have been previously linked to gluten sensitivity [4, 10, 15]. Almost half of the patients in this report (47.5%) had serological evidence of gluten sensitivity without enteropathy (coeliac disease). Gluten free diet has already been shown to be beneficial in such patients [4] and should be considered in all patients with cerebellar ataxia and sensory ganglionopathy in the presence of serological markers of sensitivity to gluten.

Declarations

Acknowledgements

None.

Funding

This is a summary of independent research supported by NIHR Sheffield Biomedical Research Centre (Translational Neuroscience). The views expressed are those of the author(s) and not necessarily those of the NIHR Sheffield Biomedical Research Centre, NHS, the NIHR or the Department of Health.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

PZ: drafting/revising the manuscript, study concept and design, data collection, statistical analysis, accepts responsibility for conduct of research and final approval. MH: drafting/revising the manuscript, study concept and design, data collection, accepts responsibility for conduct of research and final approval. PGS, DGR, NH and DS: drafting/revising the manuscript, data collection, accept responsibility for conduct of research and final approval.

Ethics approval and consent to participate

The South Yorkshire Research Ethics Committee has confirmed that no ethical approval is indicated given that all investigations were clinically indicated and did not form part of a research study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
(2)
University of Sheffield, Sheffield, UK
(3)
Department of Neuroradiology, Sheffield Teaching Hospitals NHS Foundaiton Trust, Sheffield, UK
(4)
Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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